TY - JOUR T1 - Identification and Characterization of Proximal Promoter Polymorphisms in the Human Concentrative Nucleoside Transporter 2 (<em>SLC28A2</em>) JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 699 LP - 707 DO - 10.1124/jpet.108.147207 VL - 328 IS - 3 AU - Sook Wah Yee AU - James E. Shima AU - Stephanie Hesselson AU - Loan Nguyen AU - Sarah De Val AU - Rachel J. LaFond AU - Michiko Kawamoto AU - Susan J. Johns AU - Doug Stryke AU - Pui-Yan Kwok AU - Thomas E. Ferrin AU - Brian L. Black AU - David Gurwitz AU - Nadav Ahituv AU - Kathleen M. Giacomini Y1 - 2009/03/01 UR - http://jpet.aspetjournals.org/content/328/3/699.abstract N2 - The human concentrative nucleoside transporter 2 (CNT2) plays an important role in the absorption, disposition, and biological effects of endogenous nucleosides and nucleoside analog drugs. We identified genetic variation in the basal promoter region of CNT2 and characterized the function of the variants. We screened DNA from an ethnically diverse population and identified five basal promoter variants in CNT2. Three major haplotypes in the CNT2 basal promoter region were identified and were found at different allele frequencies in various ethnic groups. The common promoter variants and haplotypes were constructed and characterized for their promoter activity using luciferase reporter assays. One polymorphic variant, rs2413775 (-146T&gt;A), with an allele frequency &gt;20% in all populations, showed a gain of function in luciferase activity. Furthermore, in vivo mouse promoter assays of these nucleotide variants using the hydrodynamic tail vein injection, leading to their expression in the liver, demonstrated similar results. Transcription factor binding site (TFBS) analysis indicated this variant alters a hepatic nuclear factor (HNF) 1 TFBS. Electrophoretic mobility shift assay demonstrated stronger binding of HNF1α and weaker binding of HNF1β to the -146T and -146A regions, whereas the single nucleotide polymorphism (SNP), -146A, exhibited enhanced binding to both HNF1α and HNF1β, consistent with its greater activity in reporter assays. The data collectively suggest that the common variant, -146T&gt;A, in the proximal promoter of CNT2 may result in an enhanced transcription rate of the gene and, thus, expression levels of CNT2. This SNP may play a role in variation in the pharmacokinetics and pharmacological effects of nucleoside analogs. The American Society for Pharmacology and Experimental Therapeutics ER -